The use of electrical stimulation to attenuate an immune response has only recently been described and has been limited to stimulation of a parasympathetic nerve. U.S. Pat. No. 6,610,713 (Tracey) demonstrated that stimulation of the parasympathetic vagus nerve prior to bacterial challenge resulted in a weakened systemic inflammatory response and was associated with greater survivability.
While intriguing, stimulation of the vagus nerve to attenuate an immune response presents several concerns. Because the vagus nerve is comprised predominantly of afferent fibers, stimulation of the vagus nerve can produce undesired, non-specific CNS effects. While U.S. Pat. No. 6,610,713 discusses selective stimulation of the efferent vagus, selective efferent stimulation will be difficult to achieve in a predominantly afferent nerve such as the vagus. Further, the vagus nerve is a “wandering” nerve that innervates several tissues in addition to the spleen, including the heart, liver and gastrointestinal tract. Accordingly, stimulation of the vagus nerve to attenuate an immune response may result in many undesired and non-specific effects.
Further, due to the complex mechanisms underlying control of an immune response, stimulation of the vagus nerve may not produce a complete or effective attenuation of a systemic inflammatory response. U.S. Pat. No. 6,610,713 suggested that the weakened systemic inflammatory response following vagus nerve stimulation was due to inhibition of pro-inflammatory cytokines through a nicotinic cholinergic receptor-mediated response. However, the parasympathetic cholinergic aspect of regulation of an inflammatory response is only one aspect of such regulation. For example, the sympathetic noradrenergic nervous system may also play a role in regulating an inflammatory immune response.
Like the parasympathetic nervous system, the sympathetic nervous system innervates the spleen, which is a major lymphoid organ. The efferent fibers of the sympathetic splenic nerve include noradrenergic neurons. Some main targets of noradrenergic innervation of the spleen include immature and mature immune cells, such as T lymphocytes, macrophages, mast cells, and plasma cells. In a normal healthy individual, the immune cells maintain a homeostasis with regard to the various factors released by the immune cells. Dysfunction of these cell types can lead to increased release of pro-inflammatory cytokines resulting in inflammation and an excessive immune response. Similarly, dysfunction in these cell types can lead to a suppressed immune response such as that observed in immunocompromised patients.
Noradrenergic agonists appear to play a role in the regulation of such cell-types. For example, norepinephrine and b-adrenergic agonists have been shown to be involved in the elimination of bacteria and may act as endogenous regulators of cytokine production in sepsis. In addition, enhanced norepinephrine levels and b-adrenergic receptor activation can decrease pro-inflammatory cytokine levels, increase anti-inflammatory cytokine levels, and alter immune effector functions during bacterial infection.
The use of electrical stimulation of a nerve or tissue associated with the sympathetic nervous system to control an immune response in vivo has not previously been described. However, as presented herein, stimulation of the sympathetic nervous system, particularly the splenic nerve, the fibers of which are predominantly efferent, may serve to attenuate an inflammatory immune response while providing less potentially undesired effects than would stimulation of the parasympathetic nervous system, particularly the vagus nerve. Furthermore, inhibition of the sympathetic nervous system may be used to strengthen an immune response when the endogenous immune response is not sufficient. Taken as a whole, varying the output of the sympathetic nervous system can serve to modulate an immune response for a desired effect thereby allowing for fine adjustments.